Significance Because the vast majority of American cities are currently out of compliance withUSEPA standards for air pollutants, most of the U.S. population lives in an environment polluted by oxidant gases. However, the impact which inspiration of these toxic gases over a lifetime has on human health, and on the principal target for the gases, the respiratory system, is poorly understood. Objectives The studies carried out by this multidisciplinary program are to define the potential of exposure to the major air pollutant, ozone, for modifying the lungs' ability to 1) resist injury from bioactivated chemical toxicants and carcinogens; 2) mount an inflammatory response to infectious agents; 3) resist injury to other inhaled toxic gases, such as nitrogen dioxide; 4) respond to challenge by agents which cause asthma. Results Long-term inhalation ozone at near ambient levels results in a diminution of the acute inflammatory response associated with initial exposure, which is called "tolerance." Animals made tolerant to ozone show marked alterations in the enzyme system, the cytochrome P450 monooxygenases, which metabolizes toxicants and carcinogens. The toxicity of a ubiquitous chemical byproduct of combustion, 1-nitronaphthalene, is highly elevated and the threshold for injury lowered in ozone-tolerant animals. Blockage of migration of neutrophils, one of the main inflammatory cells in the acute response to ozone, into respiratory bronchioles, the injury site in primates, prevents clearance of dead cells and impedes repair. Co-exposure of ozone and nitrogen dioxide produces fatal lung disease with a short-time postexposure. Short-term ozone exposure damages the nerve fibers regulating hyperreactivity of the airways associated with asthma. Future Directions To define the cellular mechanisms responsible for the elevated susceptibility to bioactivated toxicants and other oxidant gases produced by ozone exposure and the key role of neutrophils in repair of acute injury of epithelial cells and neurons following ozone exposure. KEYWORDS ozone, cytochrome P450, nitrogen dioxide, PMN, asthma, fibrosis, wound repair;